Tipped as one of the favourites to go all the way in Qatar, Fernando Santos's men will be keen to lay down an early marker and are heavily fancied to come out on top here.
The Group H clash will be just the second meeting between the teams after they had earlier faced off in the group stage of the 2014 World Cup.
Cristiano Ronaldo grabbed the winner in a 2-1 triumph 10 minutes from time after John Boye's own goal on the half-hour mark was cancelled out by Asamoah Gyan's equaliser.
However, like Ghana, the Euro 2016 winners also suffered an early exit from football's biggest tournament, which remains their worst outing at this level since 2002.
Fresh off the back of a 4-0 victory over Nigeria last Thursday, Portugal now go in search of yet another dominant display against African opponents.
Ghana will take to the field on the global stage for the first time since that aforementioned 2-1 defeat to Thursday's opponents in Brazil eight years ago.
Otto Addo's men have struggled against European teams more often than not, although they did claim a 2-0 win over Switzerland in their final warm-up fixture ahead of the World Cup.
PORTUGAL VS. GHANA HEAD-TO-HEAD RECORD
Portugal wins: 1
Ghana wins: 0
Draws: 0
Portugal goals: 2
Ghana goals: 1
MATCH HISTORY
June 26, 2014: Portugal 2-1 Ghana (World Cup)
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